Influenza Hemagglutinin Protein Stability, Activation, and Pandemic Risk

Trends Microbiol. 2018 Oct;26(10):841-853. doi: 10.1016/j.tim.2018.03.005. Epub 2018 Apr 19.

Abstract

For decades, hemagglutinin (HA) protein structure and its refolding mechanism have served as a paradigm for understanding protein-mediated membrane fusion. HA trimers are in a high-energy state and are functionally activated by low pH. Over the past decade, HA stability (or the pH at which irreversible conformational changes are triggered) has emerged as an important determinant in influenza virus host range, infectivity, transmissibility, and human pandemic potential. Here, we review HA protein structure, assays to measure its stability, measured HA stability values, residues and mutations that regulate its stability, the effect of HA stability on interspecies adaptation and transmissibility, and mechanistic insights into this process. Most importantly, HA stabilization appears to be necessary for adapting emerging influenza viruses to humans.

Keywords: fusion glycoprotein; influenza A virus; interspecies adaptation; pandemic; virus entry; virus transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Ferrets / virology
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry*
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics
  • Humans
  • Hydrogen-Ion Concentration
  • Influenza A Virus, H1N1 Subtype / chemistry*
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza, Human / transmission
  • Influenza, Human / virology
  • Membrane Fusion
  • Mutation*
  • Orthomyxoviridae Infections / veterinary
  • Orthomyxoviridae Infections / virology
  • Pandemics
  • Protein Stability
  • Protein Structure, Tertiary
  • Virus Internalization

Substances

  • Hemagglutinin Glycoproteins, Influenza Virus